Thebaine is manufactured in high yields and in a highly pure form by a multi-step manufacturing process that utilizes codeine or a codeine salt as the starting material.
Thebaine is a minor component of opium. The supply of thebaine is limited, and the demand is increasing; therefore, the price of thebaine is high.
Thebaine is an important starting material for many useful compounds, particularly 14-hydroxy-substituted morphine derivatives that are important narcotic analgesics and/or antagonists, e.g., oxycodone, oxymorphone, nalbuphine, naloxone, naltrexone and nalmefene. A very useful narcotic, which is an oripavine derivative of thebaine, is buprenorphine, which is an ideal pharmacotherapy for the treatment of cocaine opiate abuse.
The starting material for the process of the present invention is codeine or a salt thereof. Codeine along with morphine, thebaine and oripavine may be extracted from poppy strawxe2x80x94see U.S. Pat. No. 6,067,749 issued May 30, 2000 to Fist et al. Codeine is also readily prepared by the methylation of morphine, which is present in poppy straw in a higher percentage than that of codeine.
Column 1, lines 37-45 of U.S. Pat. No. 6,008,355 describe several prior art methods for preparing thebaine: For example, codeine may be converted to thebaine through codeinone or through the 6-methyl ether of codeine.
Column 1, line 44 to column 2, line 56 of U.S. Pat. No. 6,090,943 also describe a number of prior art methods for the preparation of thebaine. The ""943 patent itself discloses a process for preparing thebaine or thebaine analogs containing a dienol ester or a dienol ether, from morphinone, codeinone or analogs thereof which contain an xcex1,xcex2-unsaturated ketone via an alkoxylated intermediate.
All of the prior art methods for preparing thebaine from codeine or a salt thereof are disadvantageous from a commercial manufacturing point of view in several respects. The purity of the thebaine is relatively low, thereby requiring considerable additional costly purification steps (and attendant loss of yield) to raise the purity to an acceptable level. A second disadvantage of the prior art methods is that they require the use of expensive reagents and the reactions are very time-consuming and are quite sensitive to reaction conditions. Thirdly, and most importantly, the prior art methods results in poor yields of thebaine and therefore such methods are unsuitable for commercial manufacturing operations.
It is the principal object of this invention to prepare thebaine with a high level of purity and sufficiently high yields so as to result in a commercially feasible manufacturing operation.
The process of the invention for the manufacture of thebaine comprises the following steps:
(a) converting codeine or a codeine salt into the intermediate N-carboalkoxy- or N-carboaryloxynorcodeine;
(b) oxidizing the intermediate N-carboalkoxy- or N-carboaryloxynorcodeine to yield the intermediate N-carboalkoxy- or N-carboaryloxynorcodeine;
(c) enolizing the intermediate N-carboalkoxy- or N-carboaryloxynorcodeinone with a base and methylating the resultant enolate to yield the intermediate N-carboalkoxy- or N-carboaryloxynorthebaine; and
(d) reducing the intermediate N-carboalkoxy- or N-carboaryloxynorthebaine to yield thebaine.
Step (a) may be carried out by reacting the codeine or a codeine salt, e.g., codeine phosphate, with a chloroformate in the presence of an alkali metal carbonate or alkali metal bicarbonate and an inert solvent. Preferably, the chloroformate is a methyl, ethyl or phenylchloroformate. The alkali metal is typically sodium or potassium. Suitable examples of the inert solvent that may be used in step (a) include methylene chloride, chloroform, 1,2-dichloroethane and the like. Typically, the selected chloroformate will be utilized in an amount of about 1.5 to about 8.0 moles per mole of codeine or codeine salt. In general, the inert solvent will be present in the amount of about 10 to about 60, preferably 20 to 25, liters per kilogram of codeine or the selected codeine salt. The reaction involved in step (a) may be carried out at a temperature of about 0 to about 85xc2x0 C., preferably 42-70xc2x0 C., e.g., when the selected inert solvent is chloroform, the reaction is typically carried out under reflux at 65xc2x0 C. The reaction time will typically be in the range of about 10 to about 72 hours, preferably 10 to 24 hours. The reaction in step (a) proceeds smoothly and completion of the reaction may be determined by high-pressure liquid chromatography.
Preferably, the intermediate N-carboalkoxy- or N-carboaryloxynorcodeine is not isolated, and step (b) is carried out in the same reaction vessel as employed for step (a).
Step (b) may be carried out by oxidizing the intermediate N-carboalkoxy- or N-carboaryloxynorcodeine with a suitable oxidizing agent in the presence of an inert solvent (which may be the same inert solvent as employed in step (a)). Suitable oxidizing agents include aluminum alkoxide and a ketone; a potassium alkoxide and a ketone; dimethyl sulfoxide in the presence of oxalyl chloride; manganese dioxide; potassium dichromate in the presence of sulfuric acid; and air in the presence of palladium (II) acetate. The preferred oxidizing agent comprises manganese dioxide. In general, the oxidizing agent will be used in an amount of about 7 to about 9 moles per mole of N-carboalkoxy- or N-carboaryloxynorcodeine.
Useful inert solvents for carrying out step (b) include chlorinated hydrocarbons such as chloroform, methylene chloride, 1,2-dichloroethane and the like; hydrocarbons such as benzene or toluene; esters such as ethyl acetate; and ethers such as tetrahydrofuran. The preferred solvents are chloroform and toluene. In general, the inert solvent will be utilized in an amount of about 10 to about 50, preferably 20 to 25, liters per kg of the intermediate resulting from step (a).
The oxidation reaction of step (b) may be carried out at temperatures of about 0 to about 60xc2x0 C., preferably 20-25xc2x0 C. Typically, the oxidation reaction for step (b) will entail a reaction time of about 6 to about 48, preferably 18 to 24, hours.
Preferably, the intermediate N-carboalkoxy- or N-carboaryloxynorcodeinone produced in step (b) is not isolated, and step (c) is carried out in the same reaction vessel as employed for step (b).
In step (c), the intermediate N-carboalkoxy- or N-carboaryloxynorcodeinone produced in step (b) is enolized using a base in an inert solvent and the resultant dienolate salt is thereafter methylated using a methylating agent. Suitable bases for carrying out the enolization reaction include sodium hydride, sodium t-butoxide, potassium t-butoxide and lithium diisopropylamide. Suitable inert solvents for carrying out the enolization reaction (and the subsequent methylation reaction) include tetrahydrofuran, N-methylpyrrolidinone, dimethylformamide, toluene, dimethyl ether, methyl t-butyl ether, dioxane and the like. The preferred solvent for carrying out both the enolization and the methylation reactions in step (c) comprises a mixture of about 1 part to about 20, preferably 4 parts, of tetrahydrofuran per part of N-methylpyrrolidinone. In general, the inert solvent employed in step (c) is employed in an amount of about 10 to about 50, preferably 20 to 30, liters per kg of the intermediate N-carboalkoxy- or N-carboaryloxynorcodeinone produced in step (b).
The methylation reaction may be carried out with typical methylating agents such as dimethyl sulfate, dimethyl carbonate, methyl iodide, methyl bromide, diazomethane and the like. In general, the methylating agent will be employed in an amount of about 2 to about 4 moles per mole of N-carboalkoxy- or N-carboaryloxynorcodeinone.
The enolization reaction as well as the subsequent methylation reaction involved in step (c) are typically conducted at temperatures in the range of about xe2x88x9220 to about 50xc2x0 C., preferably xe2x88x925 to 5xc2x0 C. The typical reaction time for carrying out both the enolization reaction as well as the methylation reaction involved in step (c) will be about 2 to about 24, preferably 8 to 15, hours.
Preferably, the intermediate N-carboalkoxy- or N-carboaryloxynorthebaine produced in step (c) is not isolated, and step (d) is carried out in the same reaction vessel as employed for step (c).
In step (d), the intermediate N-carboalkoxy- or N-carboaryloxynorthebaine is reduced to yield the intermediate thebaine. The reducing agent preferably comprises lithium aluminum hydride or sodium bis(2-methoxyethoxy)aluminum hydride (boranetetrahydrofuran complex or borane-dimethyl sulfide complex may also be used). The reaction is generally carried out in an inert solvent such as tetrahydrofuran (which is preferred), dimethyl ether, diethyl ether, methyl t-butyl ether, and the like. Typically, such inert solvent will be utilized in an amount of 10 to about 50, preferably 20 to 30, liters per kg of the intermediate N-carboalkoxy- or N-carboaryloxynorthebaine produced in step (c).
In general, the reducing agent will be employed in step (d) in an amount of about 1 to about 3 moles per mole of N-carboalkoxy- or N-carboaryloxynorthebaine. In general, step (d) is carried out a temperature of about to about 60xc2x0 C., preferably 20 to 25xc2x0 C. The typical reaction time for carrying out the reduction reaction involved in step (d) will be about 1 to about 20, preferably 8-12, hours.
Preferably, the intermediate thebaine produced in step (d) is isolated as an acid addition salt. The isolation of the thebaine as an acid addition salt preferably involves the reaction of the thebaine with L-tartaric acid in a C1-C4 alcohol, acetone or a mixture thereof with water. In general, the isolation of the thebaine entails the use of about 1 to about 1.5 moles of L-tartaric acid per mole of thebaine produced in step (d). Typically, the C1-C4 alcohol, acetone or a mixture thereof with water will be utilized in an amount of about 5 to about 20, preferably 10-15, parts of such solvent per part of thebaine produced in step (d). If a mixture of the C1-C4 alcohol or acetone with water is utilized as the solvent, the water may be present in an amount of about 5 parts to about 20 parts per 100 parts of the C1-C4 alcohol or acetone. The preferred solvent is a mixture of methanol and water. The isolated thebaine bitartrate addition salt is recovered in a very high yield with a very high level of purity as a result of this isolation technique.
The following nonlimiting examples shall serve to illustrate the preferred embodiments of the present invention. Unless otherwise indicated to the contrary, amounts and percentages are on a weight basis.